The present invention relates to the 14b(R) isomers of tetracyclic compounds having two or three ring nitrogen atoms, which we have found to have valuable anti-allergic and anti-asthmatic activities, and provides methods and compositions using them, as well as processes for their preparation.
The compounds of the present invention may be generally described as dibenzo-pyrazino-azepine or benzo-pyrido-pyrazino-azepine derivatives. Certain compounds of this type are known. For example, mianserin, which has the formula (A): ##STR2## mirtazapine, which has the formula (B): ##STR3## aptazapine, which has the formula (C): ##STR4## 2-(2-hydroxyethyl)-1,3,4,14b-tetrahydro-2H, 10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine, which has the formula (D): ##STR5## 2-methoxycarbonylmethyl-1,3,4,14b-tetrahydro-2H, 10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine, which has the formula (E): ##STR6## and 2-(2-carboxamidoethyl)-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a] azepine, which has the formula (F): ##STR7## are disclosed in U.S. Pat. No. 4,025,513, U.S. Pat. No. 4,062,848, European Patent Specification No. 1585 and PCT Application No. WO-88/07997, and are said to have various activities, including anti-depressant activity and anti-histamine activity.
However, the closest prior art is believed to be European Patent Application No. 447 857, which discloses a series of tetracyclic compounds similar in structure to certain of those of the present invention. We have surprisingly discovered that those isomers of the compounds of the present invention in which the carbon atom at the 14b-position is in the R configuration are of at least equal activity and that the 14b(R) isomers are of significantly lower toxicity than the racemates described in this prior art.
The compounds referred to above which are said to possess an anti-allergic activity have been found to be not entirely satisfactory, in that the intensity of the activity is less than would be desired for a useful commercial product, and side effects, such as irritation or depression of the central nervous system, often occur. It would, therefore, be desirable to develop therapeutic agents which, whilst possessing excellent anti-histamic, anti-allergic and anti-asthmatic activities, also have no substantial adverse reactions, such as depression or irritation of the central nervous system.
We have now discovered a series of tetracyclic compounds which fulfil these various desiderata.